Detection of KRAS oncogene in peripheral blood as a predictor of the response to cetuximab plus chemotherapy in patients with metastatic colorectal cancer

Abstract

Purpose: Previously we developed membrane-arrays as a promising tool to detect circulating tumor cells (CTC)with KRAS oncogene in patientswithmalignancies.This study was conducted to determinate the predictive values of CTCs with KARS mutation by membrane-arrays for metastatic colorectal cancer patients treatedwit h cetuximab plus chemotherapy. Experimental Design: Seventy-six metastatic colorectal cancer patients receiving cetuximab plus FOLFIRI or FOLFOX-4 chemotherapy were enrolled. KRAS mutation status in the peripheral bloodof these patients was analyzed using membrane-arrays, and KRAS mutation status in tumors was analyzedby DNA sequencing. Results: Among 76 metastatic colorectal cancer patients, KRAS mutations in tumors andin peripheral bloodwere identified in 33 (43.4%) and 30 (39.5%) patients, respectively.The detection sensitivity, specificity, andacc uracy of membrane-arrays for CTCs with KRAS oncogene were 84.4%, 95.3%, and9 0.8%, respectively, and indeed a highly significant correlation to KRAS mutations in tumors (P < 0.0001)was observed. Forty-five (59.2%) patients responded to cetuximab plus chemotherapy, and4 1and4 0 were wild-type KRAS in tumors andper ipheral blood, respectively (both P < 0.0001). Patients with tumors that harbor wild-type KRAS are more likely to have a better progression-free survival ando verall survival when treated with cetuximab plus chemotherapy (P < 0.0001). Likewise, patients with CTCs of wild-type KRAS in peripheral blood express a better progression-free survival ando verall survival when treated with cetuximab plus chemotherapy (P < 0.0001). Conclusions: These findings provide evidence that detection of KRAS mutational status in CTCs, by gene expression array, has potential for clinical application in selecting metastatic colorectal cancer patients most likely to benefit from cetuximab therapy. © 2009 American Association for Cancer Research.